Metabolic diseases include obesity type 2 diabetes mellitus (insulin resistance) and non-alcoholic fatty liver disease (NAFLD). These disorders are associated with increased risk for cardiovascular diseases such as atherosclerosis and non-alcoholic steatohepatitis (NASH), and cancer. There is a marked increase in cancer risk of over 35% depending on the cancer type, associated with obesity, and insulin resistance. NAFLD and NASH are associated with markedly increased risk for liver cancer. A chronic imbalance between energy intake and energy expenditure causes obesity for which there is no safe and effective drug therapy. Bariatric surgery, such as Roux-en-Y gastric bypass and vertical sleeve gastrectomy, are among the most effective surgical treatments for obesity. The use of oral medications that frequently work on the central nervous system are associated with untoward side effects. Intestinal fat blocking agents also cause adverse effects. Farnesoid X receptor (FXR, NR1H4), a member of the nuclear receptor superfamily of transcription factors, is an important sensor and regulator of bile acid, lipid, and glucose metabolism. FXR controls enterohepatic circulation of bile acids through the regulation of bile acid synthesis and transport in the liver, and and bile acid transport in the ileum. Studies in FXR knockout mice have further revealed the important role of this receptor in the control of metabolic disease. FXR has complex roles in the pathogenesis of metabolic dysfunction in liver, intestine, adipose tissue, and kidney, and can exert different effects on metabolism. FXR was demonstrated to be an effective drug target to treat cholestasis. The FXR agonist obeticholic acid was found to improve fatty liver and cholestasis in mouse disease models. Obeticholic acid was recently approved for the treatment of Primary Biliary Cholangitis (PBC), although side effects include increased pruritus and elevated serum cholesterol and lipids. Inhibition of intestine FXR has emerged as a novel means to control metabolic disease. Recent studies in which mice made obese on a high-fat diet (HFD) were treated with the gut microbiota modifying agent tempol or antibiotics, revealed inhibition of intestinal FXR signaling and amelioration of obesity, insulin resistance and NAFLD. Alteration of the gut microbiota tempol or antibiotics led to the discovery of an natural endogenous antagonist of FXR, taurine-beta-muricholic acid (T-beta-MCA) which is produced in the liver but subjected to hydrolysis by gut bacteria through bile salt hydrolase (BSH). However, due to bacterial BSH, T-beta-MCA was unstable in the intestine of normal mice not treated with tempol or antibiotics which killed bacterial expressing BSH. These studies led to the hypothesis that antagonism of FXR in HFD-treated mice ameliorated HFD-induced obesity, insulin resistance and NAFLD. These studies led to the discovery of a new orally available, small molecule, intestine-specific FXR inhibitor, glycine-beta-muricholic acid (Gly-MCA), a bile acid that is not hydrolyzed BSH and thus stable in the intestine. Oral administration of Gly-MCA to mice at low dose once per day prevents and treats diet-induced and genetic (leptin-deficient mice) obesity, along with insulin resistance and NAFLD without systemic, hepatic or intestinal toxicities. Further studies revealed that specific inhibition of a novel intestinal FXR-ceramide axis produced striking metabolic improvement after Gly-MCA treatment. Mechanistic studies further revealed that FXR regulates genes involved in ceramide synthesis and that ceramides mediate the metabolic effects of Gly-MCA. Increased serum ceramides are known to be associated with metabolic disease in rodents and humans. Injection of ceramides to Gly-MCA-treated mice reversed the desirable metabolic effects of Gly-MCA. Specific inhibition of intestinal FXR may be a reasonable therapeutic strategy for treatment of human metabolic disorders. Finally, a study in humans revealed that obesity was positively correlated with increased FXR expression and signaling in the ileum. These studies have resulted in patents that have been filed nationally and internationally for method of use and for Gly-MCA and related derivatives, and negotiations are underway to license this technology to the private sector for drug development.